Leucopenia is a common clinical disease, and severe leucopenia can lead to the occurrence of severe infection and even death. Therefore, leucopenia in the clinic leucopenia, especially severe leucopenia was given full attention.
Leucopenia may be primary, hereditary, can also be secondary to infection and other factors, but in the clinic leucopenia induced by chemical substances, drugs, in particular cytotoxic drugs and radiotherapy is more common.
Malignant tumor is one of the most major diseases that affect human health and life. Chemotherapy, radiotherapy and surgical treatment are combinationally used as the primary means of treating malignant tumor. Cytotoxic drugs are still dominant in the cancer chemotherapy drugs at this stage. As the selectivity of such drugs is not strong, the vast majority of them all have different degrees of inhibition of the bone marrow. At present, the impact of high-dose chemotherapy, as well as multi-cycle multi-drug combinational chemotherapy for malignant tumor is widely used, which makes bone marrow suppression very common. According to the statistics, 90% of chemotherapy patients have the phenomenon of varying degrees reduction of white blood cells. The reduction of white blood cells becomes the limiting toxicity of chemotherapy drugs dose, which is the important reason of not increasing chemotherapy dose of many patients, thus directly affecting the increasing of index of chemotherapy. And the reduction of peripheral white blood cells caused by bone marrow suppression which is induced by radiotherapy is the most common and most serious complications.
These factors reduce the peripheral white blood cells, whose pathogenesis is mainly the direct injury of the hematopoietic stem cells or progenitor cells and the early cell of division phase, as well as the interference of the proliferating cycle of granulocyte. Because the half-life of the granulocyte is short and the granulocyte is updated quickly, the granulocyte showed first the reduction for the drug of bone marrow suppression. In addition, certain factors can still induce the mature barriers of stem cells or progenitor cells, can also cause granulocyte damage or consume excessively by immunological factors or non-immunological factors. There are a small number of diseases which cause neutropenia phenomenon by the expansion of granulocyte-edge pool, or the release barriers and other mechanisms.
In the clinical treatment of leucopenia, in addition to the general robustness therapy, infection control, infusion of granulocytes if necessary, the most important method is the application of drug preventing and treating the bone marrow suppression, and promoting the peripheral leukocytosis. Therefore, the class of drug has long been the hot content of the research of new drug in the world.
There are many different types of clinical medicine to stimulate the growth of white blood cells, such as vitamin B4, vitamin B6, lithium carbonate, Leucogen, shark liver alcohol, creatinine, and coenzyme A and so on. However, a large number of clinical practices proved that the efficacy of these drugs are not sure, and most are temporary, the efficacy is very little for severe neutropenia induced by radiotherapy and chemotherapy. Currently in the leucocyte-stimulating drugs with considered curative effect and rapid efficacy, only granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) play a major role in the cancer radiotherapy and chemotherapy.
But G-CSF and GM-CSF are protein peptide drugs produced through genetic engineering approaches. The disadvantages include the inconvenience of storage and transportation, easy inactivation to affect the efficacy, shorter half-life, sometimes even twice a day injection, which gives some patients great inconvenience, and more expensive price. Therefore, it has important significance to develop small molecule compounds with prevention and treatment of bone marrow suppression, promotion of leukocytosis, curative effect, and rapid efficacy.
The dithiolopyrrolone compounds are a class of 1,2-dithioleheterocyclicpentene[4,3-b]pyrrole-5(4H)-one ring compounds. The naturally occurring dithiolopyrrolone compounds have been proven to have antibacterial activity, as well as the antitumor activity. The compounds with improved structural characteristics have been reported in the literature. Webster, etc. (U.S. Pat. No. 6,020,360, WO99/12543), Godfrey and Dell (GB2170498), Kawada Shuji, etc. (JP63-284181, JP11-279179), Stachel, etc. (Helvetica Chimica Acta 2002, 85, 4453), and Webster, etc. (WO2003/080624) reported a number of dithiolopyrrolone compounds through chemical synthesis and their antibacterial and antitumor activity.